Background

After having discussed the pathophysiological mechanisms underlying diabetic vascular disease in part I (Paneni et al., 2013), this review describes the epidemiology and clinical consequences of vascular disease in diabetic patients. The efficacy of risk factor modification and antiplatelet treatment is also discusses. We here give a summary, and refer to the review article itself for details of study outcomes.

Epidemiology of diabetes and atherosclerosis

Since the late 1990s a marked increase in the prevalence of obesity and diabetes has been observed across the globe. Although it is predicted that the rates of obesity and diabetes may flatten in Europe and the United States, a continued increase is expected in Asia and Africa. Within a diabetes population, those suffering from cardiovascular (CV) disease and with proteinuria have been identified as at higher risk.

Coronary heart disease
The observation that patients with diabetes are several-fold more likely to develop myocardial infarction (MI) than matched individuals without diabetes, led to the acceptance of diabetes as a high-risk CV state requiring secondary prevention. However, two recent studies indicate that diabetes may not reach risk-equivalence for adverse CV outcomes.
Nevertheless, the observation that a majority of patients with coronary heart disease have insulin resistance or diabetes underlines the relevance of diabetes to atherosclerosis. Furthermore, adverse events associated with symptomatic coronary heart disease are more frequent in patients with diabetes than in non-diabetic patients. Complications of diabetes such as renal failure further augment the rate of adverse events.
Both the recognition by the medical community of the importance of diabetes for atherosclerosis and the efforts to modify the increased risk have improved. Better availability and application of medical therapies has been shown to reduce the risk of MI in multiple diabetic patient populations.

Stroke
Diabetes also contributes to the burden of stroke. The Emerging Risk Factors Collaboration found that diabetes was associated with a 2.27-fold increased risk of stroke, and 56% more ischemic stroke. Following a stroke diabetes hampers cognitive recovery and functional outcome and increases mortality and the risk of recurrent stroke. Implementation of effective therapies now appears to reduce the risk of stroke in diabetes, although the data on better outcome of stroke are not uniform.

Peripheral artery disease
The increasing incidence of diabetes also has consequences for the prevalence and prognosis of peripheral artery disease (PAD). In the German Epidemiological Trial on Ankle Brachial index (GETABI) elderly patients with diabetes had a higher prevalence of PAD and intermittent claudication as compared to their non-diabetic counterparts. It is as yet unknown whether aggressive risk factor modification decreases the risk of PAD in patients with type 2 DM.

Treatment of atherosclerosis in diabetes

Modification of CV risk factors has led to significant reduction of morbidity and mortality.

Hyperglycaemia
The increased CV risk is already prevalent at the first signs of increased glucose levels, even when they are still below the diagnosis threshold for diabetes. This suggests that elevated glucose levels might be an attractive therapeutic target. Several studies showed a near statistically significant reduction in CV events upon glucose-lowering treatment. Studies that compared standard (a Hb A1c of 7.0-7.9%) with intensive (Hb A1c < 6%) therapy failed to show a reduction in major CV events.
Another strategy is to target the mechanism of hyperglycaemia, such as improving insulin sensitivity rather than insulin levels. The biguanide metformin has been shown to reduce the incidence of MI and mortality in diabetic patients. Metformin is therefore the hypoglycaemic agent of choice for use in patients with type 2 DM.
Not enough data is available for other hypoglycaemic medications, including the alpha glucosidase inhibitor acarbose, incretin mimetics, dipeptidyl peptidase-4 (DPP-4) and sodium glucose co-transporter-2 (SGLT2) inhibitors, to recommend their use for reducing CV events.

Hypertension
Treatment of hypertension was the first of diabetic comorbidities that could be targeted to reduce mortality. Diabetic patients receiving more intensive treatment had reduction in stroke risk and diabetes-related death as compared to patients who received standard blood pressure control. The efficacy of antihypertensive treatment is not as durable as treatment of hyperglycaemia with metformin, the latter of which persisted over 5 years.
Although most agree on the benefits of reaching ‘optimal’ blood pressure control, it is not very clear how ‘optimal’ should be defined. Information is sparse, but a few studies led to a recommendation that patients with diabetes have their blood pressure controlled to 130/80 mmHg or lower.
Depending on the clinical situation, different antihypertensive drugs may be preferable. If the primary goal of treatment is lowering of BP, in the absence of complications of diabetes, a thiazide diuretic, dihydropyridine calcium-channel blocker, or angiotensin-converting enzyme inhibitor (ACE-I) can be good first choices (ALLHAT). Β-adrenergic blockers are associated with increased risk of stroke as compared to non-diuretic hypertensive agents. Β-adrenergic blockers are recommended for 3 years after MI and at left-ventricular dysfunction, or to treat stable angina.
Antagonists of the renin-angiotensin system are the treatment of choice if secondary prevention is the goal, because of their possible benefits beyond lowering blood pressure. Overall, ACE-I lower the incidence of vascular events in DM (HOPE, ADVANCE, EUROPA, see review for details). Angiotensin-receptor blockers (ARBs) have comparable efficacy to ACE-I after MI. Mineralocorticoid receptor inhibitors reduced mortality when compared to placebo, in diabetic patients as much as in those without DM (refer to review for details).
Recent data (NAVIGATOR, PRoFESS) however fail to show a benefit of ACE-I over placebo in reducing CV events in diabetic patients, although the ACCOMPLISH trial did show a benefit.
The preferred treatment in settings other than after MI therefore remains to be established.

Dyslipidemia
The efficacy of statins for lipid management is well established, also for diabetic patients. All diabetic patients should thus be treated with statins. Patients with renal failure form a single exception to this recommendation, since efficacy was not consistently seen in patients undergoing haemodialysis.
Other lipid-modifying agents such as fibric acid and niacin have shown neutral or conflicting results. Thus the benefit of addition of a second lipid-modifying drug remains to be established and is not recommended as standard practice.

Antiplatelet therapy
Although current guidelines recommend low-dose aspirin for primary prevention in all patients, the benefit of antiplatelet therapy in patients with diabetes but without evident atherosclerosis is becoming less clear. Several studies have found no benefit, although aspirin use may be acceptable when CV risk is larger than 1% per year based on diabetes-based risk calculation.
In patients with acute coronary syndrome aspirin reduced the frequency of reinfarction, stroke and death. Use of the more potent P2Y12 inhibitors for secondary prevention reduced risk more in diabetic patients than in non-diabetic patients. The CHARISMA trial did not find a benefit of addition of clopidogrel to aspirin as compared to aspirin alone, while the CURE trial did find a reduction in the composite of CV death, non-fatal MI and stroke. TRITON-TIMI 38 showed that the more potent prasugrel showed greater benefit in diabetics than in non-diabetic patients. The TRILOGY-ACS trial however did not show a better outcome in diabetic patients in response to prasugrel treatment. The PLATO trial showed reduction in mortality upon ticagrelor (another P2Y12 inhibitor) treatment, but this effect did not differ between diabetic and non-diabetic patients.

The benefit of risk modification in aggregate
Modifying several risk factors provides additive benefit over modifying each of the risk factors alone. Intensive treatment that attacks both haemoglobin A1c , total cholesterol, fasting serum triglycerides, systolic and diastolic blood pressure, and includes low-dose aspirin and renin-angiotensin antagonist, reduces CV and total mortality as compared with standard treatment. In fact, intensive medical therapy proved so effective that adenosine stress radionuclide myocardial perfusion imaging did not change clinical outcome, as compared to no screening (DIAD). Thus, investigation for coronary artery disease in asymptomatic patients is not needed when patients are under intensive medical treatment.
Still, a cautious approach is warranted in individual cases, as intensive treatment of hypertension and hyperglycaemia may associate with increased CV events in the diabetic population.

Coronary revascularization
The COURAGE trial showed that addition of percutaneous coronary intervention (PCI) did not reduce death and MI compared with optimal medical therapy alone, either in the entire cohort or in a diabetic subgroup. Unless patients develop acute coronary syndrome, optimal medical therapy suffices. The FREEDOM trial compared PCI with coronary bypass grafting and found that in patients with diabetes undergoing surgical bypass had a lower risk of death, non-fatal MI and non-fatal stroke.

Conclusion

Diabetes increases the risk of developing atherosclerosis, the incidence of complications thereof, and is associated with poorer outcomes of these events. Thus diabetes can be seen as a risk multiplier in atherosclerosis.
The preferred treatment approach of most patients with diabetes and stable coronary artery disease is to provide optimal medical treatment, which should included risk factor modification, antiplatelet therapy and antianginal medications. Intensive treatment has substantially ameliorated outcomes in patients with diabetes over the past decade.

Find this article on Pubmed
Find the summary of part I of this review by Paneni et al. here